Tablet and method of dissolving same



e or prssonvma *1 so 1 Walter A. Compton and Joseph M. Treneer, Elk= hart, Ind, assignors to Miles Laboratories, Kna, Elkhart, llnd., a corporation of Indiana N Drawing. Application June 19, 1942, Serial No. 447,706

'7 Claims.

This invention relates to an improvement in tablet compositions to be dissolved in water or aqueous liquids to introduce active ingredients,

such as testing agents. In particular, it relates to such tablets in which the hydroxides of the alkali metals are among the necessary ingredients. It relates particularly to analytical compositions in tablet form which are designed to dissolve directly in water solutions and, while so dissolving, provide the proper analytical reagents with possibly other necessary conditions such as alkalinity, or heat by heat of solution and/or by heat of reaction, for the indications of the presence or absence of, or the quantitative estimation of, a substance or group of substances in the original water solution, such as sugar in urine. While these analytical tablets will dissolve with little or no dimculty in some water solutions, many other water solutions contain ingredients which inhibit or prevent their solution. The mechanism of the inhibitive action of these ingredients is their deposition upon the tablets in the form of an insoluble coating which thereby effectively retards or prevents free access of the water to the tablet. When a tablet containing an alkali-metal hydroxide is placed into a solution containing such interfering ingredients, the heat evolved and/or the alkalinity of the resulting solution tends to deposit a precipitate or coagulum upon the surface of the tablet. Such deposit may encapsulate the tablet with a. water excluding film, Manifestly, the purpose of the tablet may under such circumstances be defeated. These interfering substances are defined as thosesubstances which, inthe presence of heat and/or alkalinity, are precipitated or coagulated from their original dissolved or suspended state. Substances of this nature are common constituents of such fluids as urine, cerebrospinal fluid, blood, ascitic fluid, and various other body transudates and exudates, milk, beer, etc., which are representative of the types of solutions in which analytical tablets are designed to be employed.

Specific examples of substances which interfere with solution of these tablets are albumin, mucin, and the phosphates, and other complex organic or inorganic substances whose chemical formulae are not necessarily known, and need not be defined for the purpose of applying this invention provided they satisfy the definition above regarding precipitation or coagulation by heat and/or alkalinity. The present invention is not, of course, limited in its application only to the above fluids, or to the specifically cited interfering substances, but is intended for use in connection with all water solutions containing dissolved or suspended ingredients which are precipitated or congealed by heat or alkalinity or both.

That the dimculty in dissolving such tablets in the types of solution illustrated above is due to the formation of an insoluble envelope or sheath around the tablet can be demonstrated by placingthe tablet in such a solution, and when it has failed to complete its reaction, removing it and then placing it in water. It will then fail to react or react at best sluggishly, whereas a fresh tablet of identical nature (or the same tablet broken in half so as to present a clean surface) placed in water will react briskly and completely. That the interfering substances will form such an impervious envelope or sheath around the tablet and not simply be thrown into general suspension in the liquid, where they would not interfere, is reasonable, since when the tablet is first dropped into the solution, the alkali and heat will be most concentrated in and around the. surface of the tablet. Where the action of a tablet is impeded by film formation, it may be remedied by repeatedly breaking up the undissolved residue of the tablet. lSuch remedy is impractical, and is avoided by the present invention.

It was further found that the dificulty could be prevented by first making the solution alkaline and/or hot which would throw down the precipitate or coagulum before the tablet was added and so allow the tablet to react with the balance of the water and dissolved ingredients. This, however, involved the use of an additional reagent and/or heat in the carrying out of the test, and is hence undesirable since the chief advantage gained in employing the type oftablet described above is that only one operation is necessary to carry out the test, namely, to add a tablet to the solution tobe tested.

In seeking to circumvent these difdculties it was found that if the tablet could be made to disintegrate promptly upon being introduced into the solution the much more violent reaction so produced would prevent the encapsulation from occurring, since the reaction would thus become sufficiently violent to dislodge any such precipitate or coagulum.

Among the methods tried to defeat this dimculty was the addition to the tablet oi. anhydrous or dehydrated starch which is commonly used in tablet making to provide disintegration of an otherwise very slowly soluble or difflcultly soluble tablet in water or watery solutions. The heat of reaction of a preparation of this type, however,

is sufilciently great to cause the starch to jell, I and so defeat the purpose for which it was added.

After considerable experimentation, it was found that the incorporation into the tablet of a. soluble solid acidic substance not incompatible with the purposes of the test or-with the other ingredients, such as for example citric acid, alkali metal acid citrates, tartaric acid or alkali metal acid sulfates such as sodium acid sulfate, or potassium acid sulfate, together with a normal carbonate, sesquicarbonate or bicarbonate, also not incompatible with the purposes of the test or with the other ingredients, such as for example sodium I carbonate, sodium sesquicarbonate, or sodium bicarbonate, would solve the diillculty. In other I words, the most efiective method by which to accomplish the desired end was found to be efl'ervescent disintegration. Accordingly, an improved analytical tablet made according to the present invention will contain, in addition to its analytical reagents, an effervescent couple comprising a solid soluble acidic substance such as citric acid, the alkali metal acid citrates, tartaric acid, or the alkali metal bisulfates and a carbonate such as the alkali-metal normal carbonates, sesquicarbonates or bicarbonates, chosen so that none of the ingredients or their reaction products will be nc mpatible with the purpose of the test, or the balance of the reagents.

On placing the tablet containing these additional ingredients in water, the acid reacts with the normal carbonate, sesquicarbonate, or bicarbonate, liberating C02, at and below the surface of the tablet. This escaping gas prevents the gummy precipitate or coagulum from forming an envelope on the surface of the tablet, and also tends V to disintegrate the tablet. The escaping gas creates agitation of the solution and causes mobility of the dissolving tablet in the solution, whereby fresh liquid is constantly brought to the undissolved residue of the tablet to hasten its solution. Hence, continued access of the water to the tablet is permitted, and the reaction proceeds more rapidly to completion than when no effervescent couple is used. A further advantage was found in that the tendency of eifervescence to break up the tablet and constantly to bring fresh tablet surface in contact with the water materially speeds the solution of the tablet, and thus produces a, more rapid rise in temperature, which in many such tests is an advantage. In the practice of. a specific embodiment of our invention, 1. e. in the use of a carbon-dioxide generating efiervescent couple, which couple is compatible with the test, in a tablet supplying sodium hydroxide and a reducible copper compound for detecting the presence of reducing sugar in urine or similar fluids, it was found that a more rapid generation of heat was attained. This is of great practical advantage, since it insures under all conditions that one may expect to encounter, the attainment of the necessary temperature required for complete reaction of all the available reducing sugar with the copper compound. By more quickly efl'ecting complete dissolution, less heat is lost by exposure, and hence in fact a higher final temperature is possible. This advantage is additional to the principal advantage of the invention.

We are aware that effervescent couples have been employed heretofore in tableted compositions to hasten their disintegration and solution. Therefore, we make no claim to such matter broadly. The invention specifically is directed to the solution of analytical tablets which contain as one component a substance which is essential to the contemplated test, but which, if not properly controlled, would render solution very dimcult, if not impossible. Thus, the solution of an analytical tablet containing sodium hydroxide as an essential component will be retarded or even prevented in a urine containing albumin, since the latter will tend to precipitate on the tablet as a water excluding or water-impervious envelope. By the method of the present invent on,

however, such analytical compositions are ren-. dered readily soluble, since the eflervescent action prevents the formation by coagulation of a film of the solution inhibiting ingredients upon the tablet. It is seen, then, that ourmethod for obtaining the solution of an analytical tablet is applicable to all cas s where an undesirable reaction between one of the essential components of the tablet and an interfering ingredient of the solution to be tested would tend to prevent solution by enveloping the tablet by a water-impervious film.

While it might, in the light of our disclosure, appear obvious to utilize the mechanism of offervescence to secure the desirable effect of our invention, abstract consideration of the problem will show that such was not the case. In all analytical tablets of the type with which. we have experimented, caustic alkali is present in preponderant quantity, generally in large excess of the amount required to neutralize all acidic components. The carbonate component is present in only small amount. It was questioned, therefore, whether such a composition could be made to eflervesce while maintaining therein only the usual small quantity of the effervescent couple, in view of the large amount of caustic alkali available to neutralize the acid component of the couple or even to react with the bicarbonate portion of the couple where bicarbonate is to be used. It was also thought that substantial efiervescence could not be expected in the attendant highly alkaline solution;

The presence of carbonates in the final solution after reaction has ceased, does not necessarily indicate that the acid andnormal carbonate, sesquicarbonate or bicarbonate have not reacted, and 50 carried out the purpose above described, since CO: in escaping through a strongly alkaline solution, such as would be produced by these tablets, would naturally be absorbed at least in part, depending upon the opportunity for dissolving contact.

By experimentation, however, it was demonstrated that this combination is operative.

The following examples illustrate'the use of an effervescent couple in an analytical tablet, such as is adverted to above. Formula I represents a typical composition employed for the detection of reducing sugars in water solutions. Formula II represents a typical composition used for the detection of acetone in water solutions. These formulae are merely illustrative of compositions prepared in accordance with our invention and are not to be considered in a limiting sense. Other modifications will occur to anyone skilled in the art. Y

Formula I Parts Citric acid, CGHaOl 9 Cupric sulfate, CuS04 4. 1 Sodium hydroxide, NaOH 16 Effervescent couple composed of- (a) Citric acid, CGHBOI 4 Sodium bicarbonate, NaHCOa 4 I (b) Tartaric acid, Cd-hoe 6 Sodium carbonate, Na:CO.-4 2.5

assua e For the sodium hydroxide in the above formula.

potassium hydroxide or other alkali metal hyroxides may be used.

For the effervescent couple above recited other couples, such as sodium bisulfate-potassium carbonate, citric acid-potassium bicarbonate, sodium acid citrate-lithium carbonate, etc., may be substituted. Many effervescent couples are known, and are not here claimed per so. It is to be observed that the ingredients of the tablet are in all cases to be chosen to be compatible with each other and for the purpose of the particular test to be performed by the use of the tablet.

Formula II Parts by weight Salicylaldehyde sodium bisulfite,

C'IHsOaNEHSO3 1 Tartaric acid, C4Hs06 15 Sodium carbonate, NazCO: 2.5

Sodium hydroxide, NaOH 16 The compositions of Formula I employ the caustic alkali for its high heat of solution and for its heat of reaction with the acid ingredient as well as for alkalinity. For example, when such a composition is added to a solution of a reducing sugar, the caustic alkali, by its heat of solution and the heat of its reaction with the acidic component, provides the proper temperature for the reduction of the cupric ions by the sugar. At the same time, a high degree of alkalinity is maintained in the solution.

The purpose of the caustic alkali in Formula II is primarily to provide the proper heat and alkalinity for the test.

In any case, however, solution of a tablet of these compositions will be greatly retarded, or rendered altogether impossible, by the presence of interfering substances in the solution to be tested, unless an effervescent couple is incorporated in the tablet.

It is to be understood that the caustic alkali content of the tablet is proportioned to the amount of fluid under test and the type of test.

For example, in testing urine for the presence of reducing sugar, a tablet containing 0.3 gram of sodium hydroxide is added to approximately 0.5 cc. of urine.

It may be observed that acid in proportion greater than is necessary for the effervescent coupie is present in Formula I. The. heat of reaction between the said excess of acid and the hydroxide yields heat which in addition to the heat of solution is useful in making a test for the presence of reducing sugar in urine. It is also be observed that in Formula I the acidic element of the couple is chosen to exert a function in the testitself, in that it forms a complex with the cupric ion, useful in the test.

In the specification and claims, the term a carbonate is intended generically to include the normal carbonate, a sesquicarbonate, and bicarbonate each alone or in admixture.

Having described our invention, what we claim and wish to protect by Letters Patent is:

1. A normally self-sustaining heat-generating compressed sugar-testing tablet comprising homogeneously mixed dry powdery materials including a quantity of anhydrous alkali metal hydroxide in quantity in excess of that reactive with all the remaining ingredients of the tablet and in quantity to generate heat for effecting the test, anhydrous cupric sulfate, acid for the sugar test selected from the group consistin of citric and tartaric acids, and an effervescent couple consisting of acid selected from the group consisting of citric and tartaric acids and of carbonate salt selected from the group consisting of alkali metal carbonate and alkali metal bicarbonate, said tablet being adapted to be placed in a liquid specimen to be tested for reducing sugar, which specimen may contain an ingredient tending to deposit upon and retard dissolution of the tablet, said couple functioning to generate gas and break up the tablet while the material of the tablet is dissolving in said liquid specimen and is raising the temperature of said specimen to efiect said test by forming cuprous oxide, the generation of gas avoiding exercise of any tendency of any ingredient of the specimen to deposit upon any mass of the tablet and retard its dissolution, whereby the dissolution is hastened and the attained temperature is higher by avoiding loss of heat through shorter time for dissolution.

2. A normally self-sustaining heat-generating compressed sugar-testing tablet comprising homogeneously mixed dry powdery materials including a quantity of anhydrous alkali metal hydroxide in quantity in excess of that reactive with all the remaining ingredients of the tablet and in quantity to generate heat for effectin the test,

water-soluble cupric salt, acidic material neutralizable by a portion of said hydroxide to form upon dissolution of the tablet a dissolved reducible cupric compound, and an effervescent couple consisting of water-soluble solid acid and of watersoluble salt of carbonic acid, said tablet being adapted to be placed in a liquid specimen to be tested for reducing sugar, which specimen may contain an ingredient tending to deposit upon and retard dissolution of the tablet, said couple functioning to generate gas and break up the tablet while the material of the tablet is dissolving in said liquid specimen and is raising the temperature of said specimen to effect said test by forming cuprous oxide, the generation of gas avoiding exercise of any tendency of any ingredient of the specimen to deposit upon any mass of the tablet and retard its dissolution, whereby the dissolution is hastened and the attained temperature is higher by avoiding loss of heat through shorter time for dissolution.

3. A normally self-sustaining heat-generating compressed sugar-testing tablet comprising homogeneously mixed dry powdery materials including a quantity of anhydrous alkali metal hydroxide in quantity in excess of that reactive with all the remaining ingredients of the tablet and in quantity to generate heat for effecting the test, watersoluble cupric salt, solubilizing agent selected from the group consisting of tartaric acid, citric acid, and their alkali metal salts for dissolving the reaction product of said cupric salt and said alkali metal hydroxide for supplying to the specimen a dissolved reducible cupric compound, and an effervescent couple consisting of water-soluble solid acid and of water-soluble salt of carbonic acid, said tablet being adapted to be placed in a liquid specimen to be tested for reducing sugar, which specimen may contain an ingredient tending to deposit upon and retard dissolution of the tablet, said couple functioning to generate gas and break up the tablet while the material of the tablet is dissolving in said liquid specimen and is raising the temperature of said specimen to eifect said test by forming cuprous oxide, the generation of gas avoiding exercise of any tendency of any ingredient of the specimen to deposit .upon any mass of the tablet and retard its dissolution, whereby the dissolution is hastened and the attained temperature is higher by avoiding loss of heat through shorter time for dissolution.

4. A testing tablet adapted for dissolution in an aqueous liquid to be tested, which liquid may contain an ingredient tending to retard the dissolution of the tablet by deposition thereon, and adapted to supply chemical reagent material to eflect the test, said tablet comprising dry solid ingredients in uniform distribution, including a quantity of alkali metal hydroxide which is effective in the test upon dissolution of the tablet in the liquid, and further comprising an efiervescent couple consisting of solid acid and of solid salt of carbonic acid for interaction in the presence of water to generate carbon dioxide'on contact with said liquid for breaking up the tablet, the quantity of said hydroxide being greater than that which is chemically equivalent to the active acid content of said couple, whereby said carbon dioxide is formed in the presence of undissolved hydroxide to break up the tablet and hasten its dissolution, the generation of gas being also effective to agitate the liquid and to expose fresh tablet surfaces with the avoidance of possible dissolution-retarding deposition on any solid mass of the original tablet form.

5. A testing tablet adapted for dissolution in an aqueous liquid to be tested, which liquid may contain an ingredient tending to retard the dissolution of the tablet by deposition thereon, said tablet comprising dry solid ingredients in uniform distribution, including chemical reagent material to effect the test, and further comprising alkali metal hydroxide and also an effervescent couple consisting of solid acid and of solid salt of carbonic acid for interaction in the presence of water to generate carbon dioxide on contact with said liquid for breaking up the tablet, the amount of said hydroxide in the tablet bein in excess of an amount which will neutralize the acid of the said couple, whereby said carbon dioxide is formed in the presence of undissolved ingredients of the tablet to break up the tablet and hasten its dissolution, the generation of gas being also effective to agitate the liquid and to expose fresh tablet 45 surfaces with the avoidance of possible dissolution-retarding deposition on any solid mass of the original tablet form,

6. In the method of testing a liquid specimen by adding thereto a tablet supplying chemical reagent material to dissolve in the liquid to perform a test and alkalize the resulting medium, which liquid may contain an ingredient tending to retard dissolution of the tablet by deposition thereon, the step of dissolving in said liquid specimen a tablet containing in homogeneous admixture chemical reagent material for the test including an alkalizing quantity of alkali metal hydroxide, and an efiervescent couple consisting of watersoluble solid acid and water-soluble salt of carbonic acid, the amount of said hydroxide in the tablet being in excess of an amount which will neutralize the acid of the said couple, while generating carbon dioxide in the tablet in the presence of said hydroxide, and thereby breaking up the tablet and exposing fresh surfaces thereof, with the result of avoiding the exercise of any tendency of an ingredient of said specimen to retard the dissolution of the tablet.

'7. In the method of testing a liquid specimen by adding thereto a tablet supplying chemical reagent material to dissolve in the liquid to perform a test, which liquid may contain an ingredient tending to retard dissolution of the tablet by deposition thereon, the step of dissolving in said liquid specimen a tablet containing in homogeneous admixture chemical reagent material for the test 

